Aberrant TGF-beta function has been implicated in the pathogenesis of many diseases, and it has also suggested that diminished responsiveness to TGF-beta may contribute to the process of malignant transformation. This decreased responsiveness to TGF-beta could be caused by defects not only in TGF-beta expression of activation, but also by defects in the regulation of TGF-beta receptors. Transcriptional repression of the TGF-beta type II receptor (RII) is one of the mechanisms leading to TGF-beta resistance. The newly identified epithelium-specific ets transcription factor ERT/ESX/ESE-1/ELF3/jen binds to the TGF-beta RII promoter and induces promoter activity. The human gastric cancer cell lines, which show no detectable levels of TGF-beta RII mRNA do not express ERT mRNAs. To study the molecular mechanisms of loss of ERT expression, we have cloned and characterized the human ERT promoter. We have identified a distinct positive regulatory element (-186 to -175). The positive regulatory element interacts with four distinct nuclear protein complexes, at least one of which appears to be absent in cell lines which do not express the ERT mRNA. Deletion of the positive regulatory element markedly decreased expression of the target gene, suggesting that loss of the sequence-specific DNA binding protein is responsible for the loss of ERT expression.